PL92423B1 - Isoindolino-quinoline derivs - useful as tranquillizers and anticonvulsants[FR2167217A1] - Google Patents
Isoindolino-quinoline derivs - useful as tranquillizers and anticonvulsants[FR2167217A1] Download PDFInfo
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- PL92423B1 PL92423B1 PL1972175094A PL17509472A PL92423B1 PL 92423 B1 PL92423 B1 PL 92423B1 PL 1972175094 A PL1972175094 A PL 1972175094A PL 17509472 A PL17509472 A PL 17509472A PL 92423 B1 PL92423 B1 PL 92423B1
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- carbon atoms
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- 229940125681 anticonvulsant agent Drugs 0.000 title description 2
- 239000001961 anticonvulsive agent Substances 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 7
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical class C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 125000004429 atom Chemical group 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Chemical group [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 claims 1
- WEYVCQFUGFRXOM-UHFFFAOYSA-N perazine Chemical compound C1CN(C)CCN1CCCN1C2=CC=CC=C2SC2=CC=CC=C21 WEYVCQFUGFRXOM-UHFFFAOYSA-N 0.000 claims 1
- 229960002195 perazine Drugs 0.000 claims 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 abstract description 2
- 125000005843 halogen group Chemical group 0.000 abstract 2
- FBAIGEMWTOSCRU-UHFFFAOYSA-N 4-methylpiperazine-1-carbonyl chloride Chemical compound CN1CCN(C(Cl)=O)CC1 FBAIGEMWTOSCRU-UHFFFAOYSA-N 0.000 abstract 1
- 150000001447 alkali salts Chemical class 0.000 abstract 1
- 125000003107 substituted aryl group Chemical group 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- -1 salt anion Chemical class 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GCMNJUJAKQGROZ-UHFFFAOYSA-N 1,2-Dihydroquinolin-2-imine Chemical compound C1=CC=CC2=NC(N)=CC=C21 GCMNJUJAKQGROZ-UHFFFAOYSA-N 0.000 description 1
- IBWOBEUJEJNYOA-UHFFFAOYSA-N 6-nitroquinolin-2-amine Chemical compound C1=C([N+]([O-])=O)C=CC2=NC(N)=CC=C21 IBWOBEUJEJNYOA-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001827 electrotherapy Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 229960005152 pentetrazol Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 238000011197 physicochemical method Methods 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- G—PHYSICS
- G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
- G03G—ELECTROGRAPHY; ELECTROPHOTOGRAPHY; MAGNETOGRAPHY
- G03G15/00—Apparatus for electrographic processes using a charge pattern
- G03G15/14—Apparatus for electrographic processes using a charge pattern for transferring a pattern to a second base
- G03G15/16—Apparatus for electrographic processes using a charge pattern for transferring a pattern to a second base of a toner pattern, e.g. a powder pattern, e.g. magnetic transfer
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Physics & Mathematics (AREA)
- General Physics & Mathematics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
Description
Przedmiotem wynalazku jest sposób wytwarza¬ nia nowych pochodnych izoindoliny i ich soli ad¬ dycyjnych z kwasami o ogólnym wzorze 1, w któ¬ rym X oznacza atomy lub grupy, jednakowe, lub rózne, takie jak atom wodoru i chlorowca, grupa alkilowa zawierajaca 1—4 atomów wegla, grupe alkoksylowa, której czesc alkilowa zawiera 1—4 atomów wegla i grupe nitrowa, zas Y ozinacza atomy lub grupy, jednakowe lufo rózne, takie -jak atom wodoru i chlorowca, grupe alkilowa zawie¬ rajaca 1—4 atomów wegla, grupe alkoksylowa, której czesc alkilowa zawiera 1—4 atomów we¬ gla, ,gruipe cyjanowa i grupe nitrowa.Wedlug wynalazku zwiazki o ogólnym wzorze 1 wytwarza sie dzialajac 1-metylcpiperazyna na mieszany weglan o ogólnym wzorze 2, w którym X i Y maja wyzej podane znaczenia a Ar ozinacza .grupe fenylowa, ewentualnie podstawiona grupe alkilowa zawierajaca 1—4 atomów wegla. .Reakcje prowadzi sie .zazwyczaj w rozpuszczal- iniku organicznym, takim jak aeetonitryl, w tem¬ peraturze 10—35°C.Mieszany weglan o ogólnym wzorze 2 otrzymu¬ je sie znanym sposobem dzialajac chiloromrówcza- nem o ogólnym wzorze 3, w którym Ar ma wy¬ zej podane znaczenie, na pochodna izoindoliny o ogólnym wzorze 4, w którym X i Y maja wy¬ zej okreslone znaczenie.Reakcje prowadzi sie zazwyczaj w zasadowym rozpuszczalniku organicznym, takim jak pirydy¬ na, w temperaturze ponizej 10°C.^ Pochodne izo- indoliny o wzorze ogólnym 4 wytwarza sie zna¬ nym sposobem przez redukcje czesciowa ftalimi- du o wzorze ogólnym 5, w którym Xi Y maja wy¬ zej okreslone znaczenie. Przewaznie redukcji do¬ konuje sie przy uzyciu alkalicznego borowodorku w roztworze wodnoorganicznym.Jesli rodnik ftalimiido jest podstawiony w spo¬ sób niesymetryczny, czesciowa redukcja produk¬ tu o ogólnym wzorze 5 moze prowadzic do pro¬ duktów izomerycznych, które mozna (rozdzielic metodami fizykochemicznymi, takimi jak krysta¬ lizacja frakcjonowana lulb chromatografia.Ftaliimid O' ogólnym wzorze 5 mozna otrzymac dzialajac amino-chinolina na bezwodnik ftalowy o ogólnym wzorze 6, w którym X ma wyzej okre¬ slone znaczenie.Nowe produkty o ogólnym wzorze 1 moga byc ewentualnie oczyszczone za pomoca metod fizycz¬ nych, takich jak destylacja, krystalizacja, chro¬ matografia, lub chemicznych, takich jak tworze¬ nie soli, ich krystalizacja, a nastepnie rozklad w srodowisku alkalicznym, przy czym w opera¬ cjach tych rodzaj anionu soli jest obojetny, pod warunkiem, ze jest to sól scisle okreslona i latwa do krystalizacji.Nowe produkty otrzymywane sposobem wedlug wynalazku moga byc przeksztalcone w sole addy¬ cyjne z kwasami. Sole addycyjne otrzymuje sie dzialaniem nowych zwiazków na kwasy w odpo¬ wiednich rozpuszczalnikach. Jako rozpuszczalniki organiczne stosuje sie: alkohole, ketony lub roz- 92 4233 puszczalniki chlorowane. Utworzona sól wytraca sie po ewentualnymi zatezeniu roztworu i oddzie¬ la sie ja przez filtracje lub dekantacje.Nowe produkty otrzymywane sposobem wedlug wynalazku oraz ich sole addycyjne posiadaja in¬ teresujace wlasnosci farmakologiczne. Wykazuja- one szczególna aktywnosc jako srodki uspoka¬ jajace i przeciwkonwulsyjne. Dla zwierzat (my¬ szy) sa aktywne w dawce 10—100 mg/kg przy po¬ daniu per os, zwlaszcza w nastepujacych testach: elektroterapii, wedlug 'techniki zblizonej do opi¬ sanej przez Tedeschi i j wspólprac. [J. Phanmacol, 125, 28 (1959)], drgawek wywolanych pentetrazo- lem, wedlug techniki zblizonej do opisanej przez Everetta i Richardsa [J. Phanmacol., 81; 402 T- »41fl^L^^ekitrowstrzasu; ponadmaksymalnego we- /•^ ^^aiujg'.tecl\niki|Giwinyorda i innych [J. Phasrmacol., * 106, 319 {1952)] i iodniecenie ruchowe we- | dlug techniki Courvoisiera (zaprezentowanej na l ^^J^RMn^reslfc * Lekarzy Psychiatrów i Neurologów w * *•"- ''Toucs^lw^dnjiach 8-^13.VI.1959) i Joiou (Bulletin de la Societe de Pharmacie de Lille, nr 2, styczen 1967,^. 7).Nowe zwiazki uzywa sie w medycynie badz w postaci zasad badz soli addycyjnych farmaceutycz¬ nie dopuszczalnych, tzn. nie toksycznych w stoso¬ wanych dawkach.Jako przyklady soli addycyjnych dopuszczalnych farmaceutycznie mozna przytoczyc sole kwasów mineralnych, takie jak chlorowodorki, siarczany, azotany, fosforany lub sole kwasów organicznych, takie jak octany, propioniany, bursztyniany, ben¬ zoesany, fumarany, maleindany, szczawiany, octa¬ ny teoifiiliny, salicylany, fenolotftaliniany, metyleno- ^bis-p-oksynaftoesany lub produkty podstawienia tych kwasów.Przyklad I. Do zawiesiny 20 g 2-/6-nitro-2-chi- noliloy~3-oksykarbonylofenoksyizoindolinoinu-l w 200 cm* acetoni.trylu dodano 13,6 g 1-metylopipe- razyny i mieszano w ciagu 40 godzin w tempera¬ turze okolo 20°C. Nastepnie odfittrowanp wykry¬ stalizowany produkt i przemyto go 15 om* aceto- nitirylu i 30 om* eteru izopropylowego. Po wysusze¬ niu otrzymano 18 g produktu o temperaturze top¬ nienia 210°C i zmieszano go z 250 cm* chlorku me¬ tylenu.Odfiltrowano 3 g nierozpuszczonego osadu, a otrzymany roztwór przesaczono przez 400 g silika- zelu zawartego w kolumience o srednicy 5,5 cm.Nastepnie eluowano 6000 cm* chlorku metylenu, 1000 om* mieszaniny chlorek metylenu — metanol (99:1, cz. ofoj.) i 2000 om* mieszaniny chlorek mety¬ lenu — metanol (98:2, cz. ofoj.). Wszystkie eluaty odrzucono. Dalej eluowano 2000 om* mieszaniny chlorek metylenu — metanol (98:2, cz. obj.) a otrzy¬ many roztwór odparowano do sucha pod zmniej¬ szonym cisnieniem. Pozostalosc wykrystalizowano z 70 om* dwumetytloformamidu. Otrzymano 11,1 g 3^[oksykaribonylo-/4Hmetylo-l-ipitperazynylo/]-2-/6- -nitro-i2-chinoliilo/izoiindolinonu-l o temperaturze topnienia 227°C. 2-^-nitro-2-chino izoindolinon"l otrzymano przez dodanie 0,95 g chloroimrówczanu fenylu do zawiesiny ly2 g 3-foy- 423 4 droksy-2-/6-natro-2^chinolilo/izoindolinojnu- 12 om* pirydyny, utrzymujac przy tym temperatu¬ re okolo 5°C. Po zakonczeniu dodawania miesza¬ nine reakcyjna mieszano jeszcze w ciagu 3 go- dzin w temperaturze o^olo 20°C, po czym doda¬ no 60 cm* wody. Nierozpuszczalny produkt oddzie¬ lono przez filtracje, przemyto siikcesywnie 30 om* wody, 10 cm* acetonitr^lu i 20 cm* eteru izopro¬ pylowego. Po wysuszeniu otrzymano; l& g 2-/6-ni- tro-2-chmoMlo/-3-oksykarbonylofenoksyizodndoli- nonu-1 o temperaturze ^topnienia 228—230°C. 3-hydroksy^-/6-niitro-2Hchinolilo/izoindolinon-1 o temperaturze topnienia 298°C otrzymano dzia¬ laniem borowodorku potasowego na 6-nitro-2-fta- Mmidochinoline w srodowisku wodnoimetanolowym w temperaturze okoloi 20°C. ¦ 6Hnitro-2-ftalimidochinoMne o temperaturze top¬ nienia 264°C otrzymano dzialaniem bezwodnika ftalowego na 2-amino^6-nitrochinoline w eterze dwufenylowym w temperaturze okolo 240°C. 2-airnino^-inditrochiaiOiline otrzymano metoda opi¬ sana przez H. Outhmanna [J. Prakt. Ohem., 93, 386 <1916)].Przykladu. Postepujac jak w przykladzie Ir lecz wychodzac z odpowiednich substancji wyjscio¬ wych otrzymano nastepujace produkty: — 3[oksykarfoonylo-y4-metylo-il-piperazynylo/}2-/2- ^chinolilo/iizoindolinon-l o temperaturze topnie- nia 160°C — 3[oksykarbonylo-/4-metylo-1-piperazynylo/]-2/7- -chloro-2^chinojlilo/izoindolinon-l o temperaturze topnienia 174°C, — 3[oksykaribonylo-/4-imetylo-l-piperazynylo/] -2/7- ^nitro-S-chinollilo/izoindolinon-l o temperaturze topnienia 240°C. — 3[oksykarbónylo-2-/7-metoksy-2-chmoldlo/-/4-me- tylo^l-piperazynylo/]izoindolinon-l o temperatu¬ rze topnienia 195°C.— S [oksykarbonylo-/4-(metylo^lipiperazynylo/]-2/7- Hmetyio-2Hchinoliio/ize4ndolinon-l o temperatu- . rze topnienia 162—il63°C.^ // \. (U O INzdr CL-CO-O-Ar Wzór 3 O (X)4-4 I O o Wzór 6 PLThe subject of the invention is a process for the preparation of new isoindoline derivatives and their addition salts with acids of the general formula I, in which X represents atoms or groups, identical or different, such as hydrogen and halogen, an alkyl group containing 1- 4 carbon atoms, an alkoxy group, the alkyl group of which contains 1-4 carbon atoms and a nitro group, and Y stands for identical or different atoms or groups, such as hydrogen and halogen, an alkyl group of 1-4 carbon atoms, an alkoxy group, the alkyl portion of which contains 1-4 carbon atoms, a cyano group and a nitro group. According to the invention, compounds of general formula I are prepared by treating 1-methylpiperazine on a mixed carbonate of general formula II, in which X and Y have the above and Ar is given as meaning a phenyl group, optionally substituted with an alkyl group having 1-4 carbon atoms. The reactions are usually carried out in an organic solvent, such as aeetonitrile, at a temperature of 10-35 ° C. The mixed carbonate of the general formula II is prepared in a known manner by treatment with a chloroformate of the general formula III, in which Ar is as defined above for the isoindoline derivative of formula IV, where X and Y are as defined above. The reactions are generally carried out in a basic organic solvent such as pyridine at a temperature below 10 ° C. The isoindoline derivatives of the general formula IV are prepared in a known manner by partial reduction of the phthalimide of the general formula V in which X and Y are as defined above. Usually the reduction is done with an alkaline borohydride in an organic aqueous solution. If the phthalimido radical is unsymmetrically substituted, partial reduction of the product of general formula 5 may lead to isomeric products which can be separated by physicochemical methods such as as fractionated crystallization or chromatography. Phthalimide O 'of general formula 5 can be obtained by treating the amino quinoline with phthalic anhydride of general formula VI, in which X has the meaning defined above. New products of general formula I may optionally be purified by physical methods such as distillation, crystallization, chromatography, or chemical methods such as salt formation, crystallization and subsequent decomposition in an alkaline environment, the type of salt anion being inert in these operations, provided that that it is a precisely defined salt and easy to crystallize. New products obtained by the method according to the invention can be transformed with acid addition salts. Addition salts are obtained by the action of new compounds on acids in suitable solvents. The organic solvents used are: alcohols, ketones or chlorinated solvents. The salt formed is precipitated, if the solution is concentrated, and it is separated by filtration or decantation. The new products obtained according to the invention and their addition salts have interesting pharmacological properties. They are particularly active as sedatives and anti-convulsants. For animals (mice) they are active at a dose of 10-100 mg / kg per person, especially in the following tests: electrotherapy, according to a technique similar to that described by Tedeschi and her collaboration. [J. Phanmacol, 125, 28 (1959)], pentetrazol-induced convulsions, according to a technique similar to that described by Everett and Richards [J. Phanmacol, 81; 402 T- »41fl ^ L ^^ ecitro-shock; over-maximal we- / • ^ ^^ aiujg'.tecl \ niki | Giwinyord and others [J. Phasrmacol., * 106, 319 {1952)] and motor stimulation in- | Debt of Courvoisier's technique (presented on l ^^ J ^ RMn ^ reslfc * Psychiatrists and Neurologists in * * • "- '' Toucs ^ l in ^ dnjiach 8- ^ 13.VI.1959) and Joiou (Bulletin de la Societe de Pharmacie de Lille, No. 2, Jan. 1967, ^. 7). The new compounds are used in medicine either in the form of bases or addition salts that are pharmaceutically acceptable, i.e., non-toxic in the doses used. Examples of pharmaceutically acceptable addition salts are salts of mineral acids, such as hydrochlorides, sulfates, nitrates, phosphates, or organic acid salts, such as acetates, propionates, succinates, benzoates, fumarates, maleindanes, oxalates, theoifiyl acetates, salicylates, phenolphthalates, methylene bis- p-oxynaphthoates or their substitution products Example I. To a suspension of 20 g of 2- (6-nitro-2-quinolyl ~ 3-oxycarbonylphenoxyisoindolin-1-1 in 200 cm * acetonitrile) 13.6 g of 1-methylpipe- times and stirred for 40 hours at a temperature of about 20 ° C. Sat. the precipitated crystallized product is melted and washed with 15 ml of acetonitrile and 30 ml of isopropyl ether. After drying, 18 g of the product having a melting point of 210 ° C. are obtained and mixed with 250 ml of methylene chloride. 3 g of undissolved solids are filtered off, and the obtained solution is filtered through 400 g of silica gel contained in a column of diameter 5 5 cm. Subsequently, elution was carried out with 6,000 cc of methylene chloride, 1,000 ml of a mixture of methylene chloride-methanol (99: 1, diluted) and 2000 of a mixture of methylene chloride-methanol (98: 2, diluted ). All eluates were discarded. A further 2,000 ml of methylene chloride-methanol (98: 2, v / v) mixture was eluted and the resulting solution was evaporated to dryness in vacuo. The residue was crystallized from 70 ohm * dimethylformamide. 11.1 g of 3 [oxycaribonyl- (4H-methyl-1-ipitperazinyl] -2- (6-nitro-i-2-quinolyl) isoindolinone-1 with a melting point of 227 ° C were obtained. 2 - Nitro-2-quino isoindolinone "1 was obtained by adding 0.95 g of phenyl chloroformate to a suspension of 2 g of 3-foy-423 4-dioxy-2- (6-natro-2-quinolyl) isoindolinone-12 m * pyridine while maintaining the temperature at about 5 ° C. After the addition was complete, the reaction mixture was stirred for a further 3 hours at a temperature of about 20 ° C., then 60 cm.sup.3 of water was added. It was poured by filtration, washed successively with 30 ml of water, 10 cm3 of acetonitrile and 20 cm3 of isopropyl ether. Drying gave 1 g of 2- (6-nitro-2-hops) -3-oxycarbonylphenoxyisodndol. nonu-1, mp 228-230 ° C. 3-hydroxy (6-nitro-2H-quinolyl) isoindolinone-1, mp 298 ° C, was obtained by treatment with potassium borohydride on 6-nitro-2-phta-M-quinoline in a water-methanol environment at a temperature of about 20 ° C. 6H-nitro-2-phthalimidoquinoline with a melting point of 264 ° C was obtained by the action of phthalic anhydride on 2-amino-6-nitroquinoline in ether with diphenyl at about 240 ° C. 2-airnino-inditrochiline was obtained by the method described by H. Outhmann [J. Practice. Ohem., 93, 386 <1916)]. Following the example of Ir, but starting from the appropriate starting materials, the following products were obtained: - 3 [oxycarfoonyl-γ-methyl-yl-piperazinyl)} 2- (2-quinolyl) isoindolinone-1 with a melting point of 160 ° C. - 3 [oxycarbonyl- (4-methyl-1-piperazinyl) - 2 (7- chloro-2-quinoylyl) isoindolin-1, m.p. 174 ° C, - 3 [oxycaribonyl- (4-imethyl-1-piperazinyl) [2] -2 [7-] nitro-S-quinolyl) isoindolinone-1, m.p. 240 ° C. - 3 [oxycarbonyl-2- (7-methoxy-2-chmoldlo) - (4-methyl-1-piperazinyl)] isoindolinone-1, m.p. 195 ° C. - S [oxycarbonyl- (4- ( Methyl-Lipiperazinyl] - 2 (7- H-Methyl-2H-quinolium) -Ize4ndolin-1 with a melting point of 162-il63 ° C ^ // \. (UO INzdr CL-CO-O-Ar Formula 3 O (X) 4-4 IO o Formula 6 PL
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7200650A FR2167217A1 (en) | 1972-01-10 | 1972-01-10 | Isoindolino-quinoline derivs - useful as tranquillizers and anticonvulsants |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PL92423B1 true PL92423B1 (en) | 1977-04-30 |
Family
ID=9091655
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL1972175094A PL92423B1 (en) | 1972-01-10 | 1972-12-28 | Isoindolino-quinoline derivs - useful as tranquillizers and anticonvulsants[FR2167217A1] |
| PL1972159839A PL89131B1 (en) | 1972-01-10 | 1972-12-28 | Isoindolino-quinoline derivs - useful as tranquillizers and anticonvulsants[FR2167217A1] |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL1972159839A PL89131B1 (en) | 1972-01-10 | 1972-12-28 | Isoindolino-quinoline derivs - useful as tranquillizers and anticonvulsants[FR2167217A1] |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS5622780A (en) |
| AR (1) | AR202800A1 (en) |
| AU (1) | AU468083B2 (en) |
| CS (2) | CS181717B2 (en) |
| ES (2) | ES410490A1 (en) |
| FR (1) | FR2167217A1 (en) |
| PL (2) | PL92423B1 (en) |
| SU (2) | SU488409A3 (en) |
| YU (2) | YU35766B (en) |
| ZA (1) | ZA73118B (en) |
-
1972
- 1972-01-10 FR FR7200650A patent/FR2167217A1/en active Granted
- 1972-12-28 PL PL1972175094A patent/PL92423B1/en unknown
- 1972-12-28 PL PL1972159839A patent/PL89131B1/en unknown
-
1973
- 1973-01-08 ZA ZA730118A patent/ZA73118B/en unknown
- 1973-01-08 AU AU50876/73A patent/AU468083B2/en not_active Expired
- 1973-01-10 CS CS7300000201A patent/CS181717B2/en unknown
- 1973-01-10 CS CS7600006360A patent/CS181748B2/en unknown
- 1973-01-10 ES ES410490A patent/ES410490A1/en not_active Expired
- 1973-01-10 ES ES410489A patent/ES410489A1/en not_active Expired
- 1973-01-10 SU SU1874587A patent/SU488409A3/en active
- 1973-08-23 AR AR249716A patent/AR202800A1/en active
-
1974
- 1974-06-17 SU SU2032660A patent/SU499805A3/en active
-
1979
- 1979-07-30 YU YU1847/79A patent/YU35766B/en unknown
- 1979-07-30 YU YU01874/79A patent/YU187473A/en unknown
-
1980
- 1980-07-09 JP JP9280780A patent/JPS5622780A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| SU499805A3 (en) | 1976-01-15 |
| AU5087673A (en) | 1974-07-11 |
| YU184773A (en) | 1980-10-31 |
| AR202800A1 (en) | 1975-07-24 |
| CS181717B2 (en) | 1978-03-31 |
| YU35766B (en) | 1981-06-30 |
| YU187473A (en) | 1980-10-31 |
| ZA73118B (en) | 1973-09-26 |
| PL89131B1 (en) | 1976-10-30 |
| AU468083B2 (en) | 1975-12-18 |
| FR2167217B1 (en) | 1975-06-13 |
| ES410489A1 (en) | 1975-12-01 |
| JPS5622780A (en) | 1981-03-03 |
| FR2167217A1 (en) | 1973-08-24 |
| ES410490A1 (en) | 1975-12-01 |
| SU488409A3 (en) | 1975-10-15 |
| JPS5653310B2 (en) | 1981-12-17 |
| CS181748B2 (en) | 1978-03-31 |
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